Sepsis resuscitation generally focuses on hemodynamics. Rivers of ink have been spilled writing about oxygen delivery and fluid responsiveness. This is clearly important, but it's possible that our focus on easily observable phenomena has led us to ignore something of equal importance: metabolic resuscitation. We can deliver all the oxygen we want to the tissues, but if the mitochondria are failing it won't work.

Thiamine deficiency is common in sepsis, occurring in perhaps one-third of patients. This is associated with increased mortality (Manganese 2011).

Imagine what would happen if we routinely measured vitamin levels on all of our patients. We would be alarmed by our patients' low levels. However, in practice we don't check these, so profound derangements pass unnoticed.

Vitamin deficiency causes clinical disease

Vitamin C deficiency causes scurvy. Vitamin C is important for the maintenance of endothelial boundaries, with edema noted in scurvy. Vitamin C is also required for the synthesis of catecholamines and cortisol, so deficiency causes failure of the sympathetic nervous system.

It is unclear precisely how important vitamin deficiencies may be to the pathogenesis of sepsis. However, it's not difficult to imagine that the simultaneous development of several vitamin deficiencies could synergize to promote organ failure. For example, a patient with high-output heart failure (from thiamine deficiency) and sympathetic nervous system failure (from vitamin C deficiency) would develop profound shock.

Clinical studies of IV vitamin C in critical illness

Intestinal absorption of vitamin C is saturable. Given the increased metabolic consumption of Vitamin C in critical illness, the only way to replete Vitamin C in this context is intravenously.

This is a prospective RCT involving 37 patients with major burns (>30% body surface area). Patients were randomized regarding whether or not to receive an infusion of IV vitamin C, 66 mg/kg/hr for the first 24 hours of hospitalization.

Patients were resuscitated to an identical MAP and CVP. However, patients in the vitamin C group required less fluid resuscitation, had higher urine output, and developed less wound edema (figure below). As might be expected, this translated into improved oxygenation and less time on mechanical ventilation among the Vitamin C group (average of 12 vs. 21 days of ventilation, p=0.03).

The primary endpoint was a composite of pneumonia or ARDS. Although there were trends towards fewer pulmonary complications among patients treated with antioxidants, these didn't reach statistical significance (the study was underpowered due to low rates of respiratory complications). However, patients treated with vitamins E and C fared better on a variety of secondary endpoints including less time on the ventilator and less multiorgan failure.

Secondary endpoints included SOFA score and inflammatory markers. Given the low number of patients in each arm, comparisons were made to the patients' baseline scores. Patients treated with vitamin C experienced a dose-dependent improvement in SOFA score over time (below, right). Vitamin C also improved inflammatory markers (below, left).

Since vitamin C is required for catecholamine synthesis, many authors have hypothesized that it could expedite weaning off vasopressors (Carr 2015). These investigators tested this hypothesis among 24 patients from a surgical ICU with vasopressor-dependent septic shock (tables below, left). Patients were randomized to receive placebo vs. Vitamin C 25 mg/kg IV q6hr.

The primary endpoint was vasopressor dose and duration, which were significantly reduced in patients receiving vitamin C (tables below, right). There was also a reduction in mortality among patients treated with Vitamin C.

Clinical studies of IV thiamine in sepsis

This was a RCT investigating the effect of thiamine (200 mg IV q12hr) in 88 patients with septic shock. Thiamine had no effect on lactate levels or mortality within the entire population (figure below, left). This may be explained by the fact that only 35% of the patients had thiamine deficiency. Within this pre-specified subgroup, thiamine administration did reduce lactate levels and mortality (figure below, right).

This is a before-after study investigating the impact of treating sepsis with a combination of thiamine 200 mg IV q12hr, Vitamin C 1.5 grams Q6hr, and hydrocortisone 50 mg IV q6hr. The rationale for combining steroid and Vitamin C is that they work synergistically, for example vitamin C may restore sensitivity to glucocorticoids (Marik 2016). In tissue cultures of endothelial cells, the combination of steroid and vitamin C (but neither drug in isolation) can preserve endothelial integrity against challenge from lipopolysaccharide.

This therapy was applied to patients in a medical ICU with sepsis and a procalcitonin >2 ng/ml. 47 patients were included in each group, with good matching between groups:

The primary outcome was mortality, which was substantially reduced in patients receiving vitamin C (p<0.001, figure below). Similar results were obtained when the data was analyzed via two alternative methods, using either a propensity-adjusted outcome or logistic multivariate analysis. The robustness of these analyses suggest that mortality differences reflect a true treatment effect, rather than statistical confounding.

Patients treated with Vitamin C were weaned off vasopressors much earlier than control patients, despite receiving on average a bit less fluid (figure below). This result is similar to findings discussed above from the RCT by Zabet 2016.

Patients treated with Vitamin C experienced more rapid decline in SOFA score and procalcitonin (figures below). These results are similar to results shown above from the RCT by Fowler 2014.

This study is limited by its single-center, before-after, non-blinded design. However, the patients were quite well-matched at baseline and the outcomes are objective. Two statistical analyses failed to detect confounding. The results show dramatic separation between the two groups, considerably larger differences than might be realistically explained by a Hawthorne effect.

Another limitation is that the study evaluated three simultaneous interventions. As such, it is impossible to determine which agent(s) are responsible for the clinical improvement seen. To attempt to reproduce these results clinically, this combination of three agents must be used.

This study was recently presented at the Critical Care Reviews conference:

How should we use this information?

Safety of Vitamin C and Thiamine (for a septic patient already on steroid)

The safety of IV thiamine 400 mg/day is universally accepted and not worth further discussion.

Interest in vitamin C has persisted for over half a century, so its safety is well established even at enormous doses. For example, none of the above studies reported any adverse event, despite the use of massive doses by Tanaka et al. (1.6 grams/kg over 24 hours).

One potential concern regarding vitamin C is that it may be metabolized into oxalic acid, leading to calcium oxalate nephropathy. This doesn't seem to be a significant problem using Marik's treatment regimen, for several reasons:

Oxalate formation is a dose-dependent toxicity. This has rarely been reported from short courses of IV vitamin C, but only at much higher doses (>40 grams/day; Buehner 2016).

Concurrent use of thiamine should reduce the conversion of vitamin C into oxalate.

In Marik's study, Vitamin C use correlated with improved renal outcomes (the rate of dialysis was reduced from 33% to 10%, p=0.02).

Another concern which has been raised is that vitamin C at extremely high doses may have a pro-oxidant effect. This was shown not to occur even at a dose of 7.5 grams IV daily (Muhlhofer 2004).

Ready for prime time?

This is a controversial question, which will undoubtedly leave practitioners with divided opinions. When exactly do we reach a tipping point, beyond which we feel that there is enough evidence to implement a therapy? This is almost more of a philosophical question than a scientific one, making it impossible to reach consensus. Hardcore evidence-based medicine disciples may be aghast at using a therapy without a large multi-center RCT, whereas more integrative, theoretically-minded clinicians may be willing to consider it.

It would certainly be nice to have a large, multicenter, placebo-controlled RCT. However, not every therapy requires one. The use of vitamin C to treat scurvy is based on a single-center open-label trial involving twelve sailors. There isn't any RCT proving that potassium should be repleted among patients with septic shock. Replacing an essential endogenous substance which is deficient doesn't necessarily mandate level-I evidence.

Although a single unassailable RCT is lacking, an extensive body of evidence does exist regarding vitamin C and thiamine. Over a half-century of experimentation attests to the safety of these vitamins. Several RCTs suggest that they are beneficial in critical illness, as reviewed above. Marik's results have similarities to prior RCTs, implying replicability. This clinical evidence is supported by robust basic science.

Clinical practice isn't scientifically perfect. Nearly all of our current therapies for sepsis lack level-I evidence. On the front lines of critical care, we are forced to treat dying patients based on the evidence that we have, not the evidence that we might wish for. In the context of this imperfect reality, treating septic patients with Vitamin C and thiamine may be a rational and evidence-based practice. Indeed, some authors recommended using IV vitamin C even before Marik's study was released (Honore 2016).

Septic patients are invariably deficient in Vitamin C, and frequently deficient in thiamine.

Deficiencies in Vitamin C and thiamine might explain many of the abnormalities seen in sepsis.

Vitamin C and thiamine have an outstanding track record of safety, proven over decades of experimentation and clinical experience.

Five RCTs have suggested benefit from Vitamin C or thiamine in critically ill patients, with no evidence of toxicity.

A recent before-after study found a substantial mortality benefit from the combination of stress-dose steroid, IV vitamin C, and IV thiamine. Although this isn't an RCT, the results are quite striking.

Further research is required, but in the interim this is a reasonable intervention given the excellent safety profile of these agents.

Expert Commentary

Below are some additional thoughts and clinical updates from Dr. Marik. As he reports ongoing success with growing numbers of patients, it is increasingly difficult to dismiss this as a statistical or methodological fluke. Dr. Marik also shared a video with me, which is shown below. I like this video because it places this therapy into a real-life context: this isn't a futuristic theoretical treatment, it's something that's being done right now as standard-of-care at several Virginia hospitals.

We have now treated over 150 patients with severe sepsis and septic shock. We have had only one patient die from sepsis, this being a complex surgical case who died in the immediate post-operative period. While a few of the treated patients have died, none died from progressive organ failure related to sepsis. All these patients were weaned off pressors/mechanical ventilation and died from their underlying disease. There can be no question of doubt that we have changed the natural history and disease progression of patients with sepsis… patients with sepsis simply just don’t develop progressive organ failure.

The cocktail is without side effects; renal function has improved in all treated patients. On average patients receive 3-4 days of treatment with the cocktail which is then stopped on discharge from the ICU or day 4. Typically patients with septic shock who are admitted to our ICU are discharged on the third ICU day with minimal organ failure (low SOFA Score).

The protocol is initiated by our residents in the Emergency Room at the same time that they start antibiotics. Our CEO and CMO has confirmed our results (shorter LOS and fewer deaths) and has requested that the protocol be instituted throughout our hospital system.

It is noteworthy that all animals (except human and guinea pigs) produce Vitamin C during stress and this has been shown to be protective during infection. GULO knockout mice (Vitamin C knockout mice) are much more likely to die from sepsis than wild type mice… treatment of infected GULO mice with Vitamin C is largely protective against death.

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Comment Here

Hi The recent EGDT studies (http://www.nejm.org/doi/pdf/10.1056/NEJMoa1701380) found that septic shock patients, across many centers in many countries around the world, have 25% mortality at 90 days. However, Marik’s control group – though less than half required vasopressors (slightly less than the EGDT studies) – had a disturbing 40% mortality. Either these are not typical septic shock patients or something else is wrong (chance, systemic bias, or differences in baseline care at the study institution) . The high predicted mortality using APACHE-IV in both groups may suggest the former. Are they actually treating a group of vitamin-deficient patients who happen to have sepsis, or vice versa? Is this a statistical fluke given the small numbers? Did other processes of care change before-and-after (I’d hope so if the mortality was as bad as 40%!)? Is the study affected by the unblinded, non-randomised care of “believers”? This study is hypothesis generating, not practice changing. Based on the above the likelihood of this cocktail being a magic bullet for sepsis is very, very low. To think otherwise is Tooth Fairy Science. Paul Marik is a noted skeptic of other studies that have been subject to ‘medical reversal (Rivers, Leuven I), it worries me that… Read more »

Excellent points, well taken. I agree that at this point the truth cannot be known with certainty.

What about the following points, though:

(1) Currently Marik is reporting a series of 150 septic patients with none experiencing sepsis-related mortality. That’s remarkable, regardless of what his baseline mortality rate is. If he is treating a very sick population, then this statistic is even more impressive. This effect size seems too large to explain based on a Hawthorne effect or bias.

(2) What about Fowler 2014 and Zabet 2016? Were these studies incorrect too?

Hi Some thoughts on your 2 points: (1) How does Marik determine what “sepsis-related mortality” is? This is potentially a ‘can-of-worms-causing-bias”… I guess the gold standard would be autopsy and path specimens analysed by independent clinicians who were blinded to the therapy received. In Australia at least, intensivists only seem to agree on the most likely proximate cause of death about 75% of the time (https://www.ncbi.nlm.nih.gov/pubmed/26947416) – and that is only a measure of agreement, not accuracy. In a 1985 NEJM study, autopsy results showed a different cause of death to death certificates in 29% of cases (https://www.ncbi.nlm.nih.gov/pubmed/4058507). If we want to make unassailable claims about mortality, we need to talk about all-cause mortality, ideally in the context of a proper trial free from bias. (2) Fowler 2014 and Zebet 2016 are TINY phase 1 trials – both trials had only 28 patients. The purpose of phase I trials is to lead onto better studies. The vast majority of Phase I trials fall by the wayside when better trials are performed. That is why we shouldn’t change clinical practice based on phase I trials. — I’d love this cocktail therapy to work as much as the next person! Unfortunately, the… Read more »

Hi Josh Re: (1) The “small study effect” is well known in epidemiology: small trials tend to produce different results, usually with larger and more “positive” outcomes, than larger trials (Sterne et al 2000; https://www.ncbi.nlm.nih.gov/pubmed/11106885; see also Nuesch et al, 2010 https://www.ncbi.nlm.nih.gov/pubmed/20639294 and Rerkasam and Rothwell, 2010 https://www.ncbi.nlm.nih.gov/pubmed/20155790 ). This occurs for numerous reasons explained in those articles. Remaining sceptical of the results of these *tiny* RCTs is simply rational behaviour. Ramesh Natarajan has a comment below. He says that Fowler has a Phase II trial underway. That is the correct response: do not stop after a small Phase I trial, follow it up with better trials to try to find out whether the effect is real. Re: (2) You have made a strawman argument against me here. At no stage have I questioned the safety profile of Vitamin C specifically. Having said that, it isn’t inconceivable that there could be side effects or unintended consequences that are yet to be identified in the *specific* context of the treatment of septic shock. Steroids on the other hand certainly do have side-effects. The ADRENAL study (about 4000 patients…) is very nearly completed and will give us the best information yet on… Read more »

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1 year ago

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Ramesh Natarajan

Hi,

Just want to point out that there is a huge difference in oral vs intravenous vitamin C. A majority of the >57,000 citations use oral vitamin C. The intravenous route is the pharmacological route and is capable of producing high circulating levels of vitamin C. Oral vitamin, no matter how high the dose, will never give >150 – 200µM in circulation due to efficient excretion. This is circumvented by intravenous/parenteral routes. Would refer you to work by Mark Levine et al at NIH (Padayatty SJ, Sun H, Wang Y, Riordan HD, Hewitt SM, Katz A, Wesley RA and Levine M (2004). Vitamin C pharmacokinetics: implications for oral and intravenous use. Ann Intern Med 140: 533-7.)

EGDT was supported by a much stronger study with much less spectacular results, and it became the standard of care. Now we know from the recent PRISM meta-analysis it doesn’t really work. So much for proof. And it took 16 years to reverse that. I do like that unlike some critics who waffle, you have taken a stand. You are virtually certain that Dr. Marik is wrong. The real question now is how will this be tested. If even only 100 doctors or hospitals adopt this treatment right now because of Marik’s article, wouldn’t we know in a couple of months whether it is really working or not? And if you are a doctor who has chosen to treat this way, Marik says you should see improvement in less than a day. So why not do something for less than a day that might work? You wouldn’t do it if it wasn’t safe. But are there real questions of safety here or just an over abundance of caution?

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1 year ago

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Mladen S.

I do not agree that EGDT doesn’t work. Almost all subsequent studies that showed no difference between control and treatment groups practically had 60% of original EGDT goals completed in control groups. Certainly, we learned that some of the components of EGDT were bogus but, to be honest, I don’t think I ever transfused a septic patient even back in the 2000’s, when EGDT was all the rage.

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1 year ago

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Ramesh Natarajan

I am one of the authors of the original Phase 1 study in sepsis that showed reduction in organ dysfunction and attenuation of inflammatory Biomarkers. I also did many of the pre-clinical studies in mice, including the GULO mice, to show how vitamin C works in sepsis. Dr. Fowler, at Virginia Commonwealth University conducted the Phase 1 trial that showed the safety of intravenous vitamin C. Dr. Fowler is currently conducting a NIH funded Phase II multi-center RCT looking at Vitamin C in sepsis induced acute lung injury.. This trial will be completed in a few months and we should have results soon. Stay tuned.

Thank you so much for your outstanding work. Can’t wait to hear about the new trial results.

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1 year ago

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Tim Baptist

Thank you for putting this together. Based on the current evidence, likely the best answer for whether the Vitamin C cocktail works or not is “I don’t know.” Imagine two parallel universes, where in each universe, 3-4 years from now, large multicenter RCTs have clearly provided the answer to whether the cocktail works.

Universe 1: Cocktail works
– Early adopters: Saved lives
– Skeptics: Lost lives that could have been saved
Universe 2: Cocktail doesn’t work
– Early adopters; No lives saved; No to minimal harm done.
– Skeptics; No lives saved. No harm done.

If you didn’t know which universe you would end up in, would you choose to be an early adopter or a skeptic? While we are all a little skeptic, not becoming an early adopter while waiting for definitive evidence is a strategy with little to gain and much to lose.

Tim Baptist
Intensivist, Benefis Health System
@Tim_Baptist

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1 year ago

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Peter Lipowicz

I am glad somebody said this. Dr. Marik is an experienced doctor who has published many articles on sepsis. He is staking his reputation on a radical new therapy. Doesn’t it make more sense to try it than to wait three or more years for proof?

Personally, I’d rather risk looking like a fool (universe #2) than fail to use a life-saving therapy (universe #1).

With regards to Dr. Marik, it is worth noting that he has nothing to gain here and much to lose (if this doesn’t pan out).

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1 year ago

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Michael Jasumback

Tim,

Problem is, we don’t know that in universe 2, no harm is done. A 47 pt case series is not what I like to base pt care on. How many lives were lost to all of the interventions that we thought caused no harm…
Blood Transfusion for Hgb=10
Large volume fluid resuscitation
Hyperventilation
Decompressive Craniectomy
etc. etc.

And, in fact, we continue to fall into the fallacy that what Marik has published is true! A 47 pt case series, with a selected retrospective control group, CANNOT give us an answer. It can only propose a hypothesis. This is the same level of data that resulted in Ketamine being virtually banned for 20+ years.

It’s hard for me to hear the theoretical risks of vitamin C (confirmed generally safe) being compared to decompressive craniotomy and bleed-inducing APC as other treatments we “fell for” based on early data. Backed up by the argument that we’re going to waste resources, clog up our pharmacies and exhaust our nurses giving vitamin C added on to the hydrocortisone they’re giving q6h anyway? That does not seem reality-based to me. It seems more fear-driven, an effort to hold the fort and keep the barbarians (community physicians like me) from the gate, so they don’t pillage the treasures within (treatments pronounced “appropriate” by the academic establishment after exhaustive review) and break the established order of things (we all wait with bated breath until we are instructed to proceed by editorial pieces in major journals). That’s what everyone is so up in arms about: Paul broke the rules and talked to NPR first. Of course, that order was established for good reasons. Treatments can be dangerous. Care needs to be generally standardized and based on good evidence. But there are cases where the rules get bent. ART for AIDS in the 80s and 90s was one example. Compassionate use is an… Read more »

Couldn’t agree more. Fear about vitamin C seems overblown. There is always a possibility that some previously unknown side-effect will come to light. This is true when using *any* medication (particularly a new medication). Nothing in medicine is 100% safe. It’s odd that emergency/ICU docs would be afraid of vitamin C, given that we routinely use powerful drugs with lots of side-effects. Large-scale clinical trialists would like to establish a world order marked by the following features: – All studies that aren’t a large-scale RCT are regarded as inferior and dismissed automatically. – Multi-center RCTs are announced in advance, released with great fanfare, published in major journals, and worshipped as the ultimate truth. Marik’s study threatens this world order. For example, if Marik’s therapy works, then the ADRENAL study could be rendered largely irrelevant. Folks who have worked on the ADRENAL trial for the past several years probably aren’t too excited about this possibility. Don’t get me wrong, I have great respect for RCTs and obviously agree that they have helped us enormously in the past. However, I disagree with the belief that only large-scale RCTs matter (and all other types of studies are worthless). Since large-scale RCTs take many… Read more »

I agree – a lot of the reasons presented against using this protocol don’t stand up against the argument of “but the patient might not die.” There has to be room between accepting this single observational data and demanding a large scale RCT. Animal studies, a registry, or more before/after studies in other ICUs *of the exact same protocol* come to mind. They would not have the same time / expense and could provide more clarity until an RCT of some sort is done (Perhaps the sequential design suggested on fluidphysiology.org). The world order is being threatened, and that is not necessarily a bad thing because slow adoption of effective therapies kills patients. Something does feel off to me, though. If I had to put it into words I would say it is this: The manuscript was accepted on November 16, 2016. The Media efforts by EVMS appear to have been published March 23, 2017. In the 4 months in between, there is no apparent effort to confirm *in any way* the results. Sure an RCT could not have been done, but a registry could have been set up in this time in preparation for the media push. If there… Read more »

Agree, needs to be some middle-ground between accepting something as fact versus rejecting it out-of-hand.

As far as your reservations, four months is a short period of time to publish any sort of study (considering IRB approval, submission to journals, revisions, etc.). EVMS may have wanted to make sure the therapy worked on 50-100 more patients before making a big public statement.

Wish I could have made the argument half as well. Please keep us updated with the Norfolk Protocol roll-out in the USA. Many Experts here in UK nailing their colours to the mast of RCCT before adoption. Our friends at LITFL have uncontroversially noted WHEN AN RCT SHOULD NOT BE PERFORMED. – When unnecessary. – If the effect of an intervention is dramatic. https://lifeinthefastlane.com/ccc/randomised-control-trials/

Thanks. I would additionally note that two RCTs *have* been done on vitamin C in sepsis (Fowler 2014 and Zabet 2016, discussed above). These aren’t large multi-center RCTs, but they are RCTs nonetheless.

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1 year ago

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James Leo, MD, FACP, FCCP

Much of what Christopher Nickson states is fair criticism, but I don’t agree that this is “tooth fairy science”. Marik shows a plausible biochemical mechanism by which the steroids, Vitamin C, and thiamine may be synergistic and by which they may, in fact, augment endothelial integrity.

As we consider in which patients it is ethical to start this treatment in the absence of a RCT, I am troubled by the absence of discussion about potential harms of steroids in patients for whom it has not been shown to be beneficial. Given the apparent benignity of IV vitamin C and thiamine, it seems to me that there is no ethical issue in starting the Marik cocktail on vasopressor-resistant septic shock (i.e., those patients in whom steroids are already being given in accordance with the SSC guidelines). Giving the cocktail to other patients, in whom steroids would not otherwise be used, does increase the likelihood of hyperglycemia and secondary infection (particularly in severe sepsis patients). I’m interested in others’ thoughts about the ethics of implementation in these groups.

If I had to bet, I would put my money on #2. However, given the excellent price and side-effect profile, even if metabolic resuscitation is only moderately effective, this could still be an enormously valuable therapy.

(1) how strong is the evidence? (very weak)
(2) what should be the threshold for adoption?

There should be no debate that the evidence provided is very weak (as discussed in my first comment).

But, what about (2), is it worth adopting – the therapies seem safe, they’re cheap, what is there to lose?

The problem with small, poorly designed studies is that if you do enough of them you will likely generate all possible outcomes. For instance, it would be easy to produce small before-and-after studies that show that aromatherapy q2hourly and homeopathy works (through the Hawthorne effect, non-blinded believers, chance, etc). If so, should we do all of these things too – aren’t they “safe”? Where do we draw the line?

We also have to remember that adverse effects are only found reliabily when there is systematic monitoring. Furthermore, I wouldn’t want steroids unless I really needed them – they have real side-effects.

The best answer is to investigate this ‘cocktail’ further in a well-designed trial. If it works great, if not lets move on and continue to be wary about exciting, appealing claims based on little evidence.

James, you are right in that I have used a non-classic definition of Tooth Fairy Science. Harriet Hall used the term to refer to “doing research on a phenomenon before establishing that the phenomenon exists”. In some sense this is true for the Marik study – is it treating vitamin deficiency or sepsis? The problem with steroids and vitamins is that they are so ubiquitous in their effects in the body that they can be used to explain almost anything – e.g. antioxidants are the potential cure for anything.

One of the key principles of Science Based Medicine (a proposed modification of EBM) is that we need to consider prior plausibility. I think we need to consider both biological plausibility and the plausibility of the claim itself. The biological plausibility is debatable – some will be more convinced than others – but the most likely explanation for the claim of marked benefit is, unfortunately but undoubtedly, poor study design.

Chris Nickson
Intensivist, Alfred ICU
@precordialthump

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1 year ago

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Michael Jasumback

Extraordinarily well phrased commentary. This has clearly exposited an ethical dilemma that is on the cutting edge of trial ethics. Can we withhold a potentially life saving therapy with (probably) benign side effects based on limited study data. I would point out the following;
Rivers, thought he understood the pathophysiology, and applied the best therapy he could based on his understanding of the physiology at hand
We hyperventilated people for years, believing we understood the pathophysiology of our ,benign, intervention
We prescribe STATINS, and host of other medications, believing we understand their actions, benefits and risks
HAVE WE LEARNED NOTHING?
Michael A. Jasumback, MD FACEP
Medical Director
Benefis Mercy Flight
PHI Air Medical

We have been wrong about many things in the past, for sure (e.g. EGDT). However, the history of medicine is also rife with examples of late adoption causing valuable therapies to go unused for years or decades (e.g. Dr. Semmelweis and sterile technique).

The goal of this post isn’t to make any recommendation regarding whether to do this. Currently I believe it is entirely reasonable to use this therapy. However, in the absence of proof, it is also entirely reasonable *not* to use this therapy.

I would encourage folks to look at the evidence and read all the papers (not just Marik’s study). Then do what you feel is the best thing for your patients. Opinions and practice will vary, this is the nature of critical care medicine.

Josh – excellent post as always and really made me stop and think before I completed my critique.
I agree with Nickson’s comments, though. Before and after, retrospective, single center, single provider simply introduces too many biases. Did these patients simply do well because of the extraordinary doctor who was caring for them and likely paying even more attention than usual because the group was being studied? This type of intervention is ripe for the Hawthorne effect. How will this translate to other centers?
A large part of the endorsement of the therapy is the fact that it’s cheap and has minimal, if any, side effects (with the possible exception of the steroids which may have slightly more side effects). What would happen if these treatments became expensive? Clearly there is recent precedent for cheap drugs becoming expensive.
Had this study not shown up on NPR + mainstream media as a “sepsis cure”, I don’t think any of us would care too much and we’d simply say, “huh, interesting. I’ll wait for the larger RCT.” Because of how it was taken up, there are extreme views on both ends.
Thank you again not only for the analysis but all the background on the treatments.

Thanks, this is a tricky topic. Some of my thoughts on Nickson’s comments are above. NPR beat me to the punch, but this blog was already written before they posted their story. My first response when hearing about Marik’s study was precisely that: “sounds interesting, I’ll wait for a larger RCT.” However, after looking at the total body of knowledge including prior RCTs, as well as further success of Marik’s therapy post-publication, it’s seems hard to explain this all as a fluke.

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1 year ago

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Jeffrey Bilyk

Doc, I think you nailed it. Questioning everything is good. But I think the near murder of paul here is unfounded and media related. Let’s study more and move on.

Thank you for this post Josh. I would like to see these results confirmed in some way. Perhaps more before/after studies by institutions, or an RCT with sequential analysis, or a registry of patients, or animal studies. The cost data stated by EVMS of $60 for a total course of therapy is off a bit. I come up with $528. If the mortality effect in this observational trial is true, then the number needed to treat to save one life is 3. Despite the stated cost of a course of therapy being off by an order of magnitude, spending $1500 on any therapy to prevent a patient death is an incredibly low cost. The mortality benefit would have to be reduced to 0.5% before the cost to prevent the death of one patient exceeded $100,000. I think in this case the high mortality in the control group is not a particular cause for concern. The patients in the treatment group had very high APACHE-IV scores, with a predicted mortality of 39.7%. In order to find appropriately matched controls, the control group needed to have similarly high APACHE-IV scores, with a predicted mortality of 41.6%. Actual mortality in the control group… Read more »

Thanks, Joe. Agree, more data is needed and will hopefully be forthcoming soon.

Also agree that the high mortality rate in Marik’s ICU isn’t a big issue. Mortality rates may vary between different ICUs based on case mix, presence/absence of a stepdown unit, referral patterns, etc. The Apache IV predicted mortality addresses this well, also the two groups were well matched in terms of other attributes.

If the cocktail reduces the need for dialysis & duration of ICU stay, it should be cost-saving. Your analysis also points out that even if the therapy isn’t nearly as effective as Marik suggests, it would still be worthwhile.

Hi The mortality rate is potentially an issue. Remember that the APACHE scores are based on old data and that sepsis mortality has improved over time (https://www.ncbi.nlm.nih.gov/pubmed/24638143). In Australian ICUs at least, we would be concerned if our mortality was as bad as that predicted by the APACHE score, which is why we use SMRs to compare ICU outcomes and the ANZROD tool has been developed. If I looked at my unit’s performance and found mortality was that bad I would look at all aspects of processes of care to see what could be improved. Everyone in the unit would be in a heightened state, thinking ‘how can we do things better?’. I’d consider running a trial just to take advantage of the Hawthorne effect! This is one of the best reasons to be involved in trials, regardless of whether you get the control or the therapy, the attention to detail means that both groups get better care. Unfortunately, all of this will mean that a ‘before-and-after’ design will tend over-estimate the benefit of the therapy that is introduced. If you add in the huge boost to staff morale of the legendary Dr Marik walking around the unit with a… Read more »

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1 year ago

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Rohan Bussell

“If I looked at my unit’s performance and found mortality was that bad I would look at all aspects of processes of care to see what could be improved. ”
Dr Marik did mention that morbid obesity was a demographic in his area, so theres that to consider.
Secondly, being triggered to look for improvements is a great idea, depending of course on how its implemented and how well it performs. However, what I think it most interesting about the employment of an AA protocol for treatment of sepsis is how it doesnt just provide an incremental improvement, but a cure.
Obviously its hard to believe, but it gets easier to understand when you realize that AA is a multipurpose vitamin, for example Dr Marik referred to it as having hormone effects. Because it is ‘pleiotropistic’ it is integral to the correct function of neurons, phagocytes, the adrenal glands, complements/recharges GSH, scavenges, cytokine regulation and there are probably more roles that I have missed.
I think IV AA couldve been justified on the GSH depletion problem alone: “Erythrocyte GSH and serum PON1 activity levels were significantly lower in patients with mild and severe sepsis compared to those in the control group”.https://jidc.org/index.php/journal/article/view/27801365/1590

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1 year ago

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Paul

It’s very interesting and is sending ripples through the EM/CC world. Seems analogous to phosphate levels in the critically ill patient. Phosphate is required for energy metabolism, severe deficiency leads to metabolic/hemodynamic failure. We trend levels and anticipate, that especially in the setting of critical illness and/or combined nutritional deficiency, even an initial phosphate level might not remain elevated and we need to be aggressive in repletement. Maybe vitamin C is the same…

So Josh, will you be using Vitamin C on your next refractory septic shock patient?

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1 year ago

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LeShea

It seems that we would want to get the ED onboard to do this….it seems that it is the way Dr Marik poses as the way to administer the therapy (early treatment as with antibiotics being an early treatment within 1hr of diagnosis of sepsis)

Timing may play a part in how effective the treatment is as well as WHAT the treatment is.

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1 year ago

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Bill Clark, PA-C

” Rivers of ink have been spilled writing about oxygen delivery and fluid responsiveness.”
Alluding to the Rivers EGDT study or just an accidental choice of words?

I see both sides of the argument. On the one hand this is clearly an imperfect study and should convince no one of the truth of vit C/thiamine/hydrocort. On the other hand we’re not lawyers, and we needn’t be operating on a “beyond a reasonable doubt” evidential criteria. We practice in the real world with very real holes in our knowledge, and its probably correct to act so long as we believe the benefits sufficiently outweigh the risks. In this case it may in fact be correct to give our next pt with sepsis and a PCT >2 ng/ml the cocktail since the risks of Vit C and thiamine do seem to be negligible–except I’m not sure we can say the same thing about steroids? I genuinely don’t know the answer to this…there is lots of evidence that it is fairly safe if given at low doses for short periods and to relatively few people (ie the few thousand patients that comprise the entire corpus of steroids in sepsis/ARDS/Pna literature. I’m just sure it’s so innocuous as to allow us to start giving it to all our septic patients tomorrow and expect no harm. Best estimates are somewhere around 500,000-1,000,000… Read more »

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1 year ago

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CC Abbott

Hi Josh, thank you for the article. I am not a MD and certainly do not know how to argue back-and-forth about scientific methods or RCTs. However, one thing I am certain that if I or any of my family members ever end up in the hospital down with sepsis. I surely hope that my MD will not be waiting for the RCT results before trying this treatment on me or loved ones to save our lives.

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1 year ago

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CC Abbott

As I read more discussion on line, many skeptics expressed that there might be some unknown harm at this stage due to the limitations of the small study. Whatever ‘harm’, real or imaginary, associated with this Vitamins treatment is, how can it possibly be worse than the certain ‘death’ faced by millions of people globally now? Why is the burden of proof on Dr. Marik’s shoulder? Would any of these skeptical ICU doctors volunteer their loved ones in the placebo group for a larger RCT? While they argue all day long of the merits or limits of the study, or wait for the result of RCT to satisfy their need for scientific ‘proof’, millions will die. (or close to home, 1000 per day in US, 10,000 sepsis death in Canada). What is the purpose and priority of any medical pratice?

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1 year ago

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CC Abbott

correction: 10,000 death annually in Canada of 30,000 patients diagnosed of sepsis.

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1 year ago

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andrew

Metabolic Theory of Septic Shock
Please do a search for the above
Core tip: For decades septic shock has been attributed to an over-active immune response. However, immune modulation has failed to reduce mortality, casting doubt on a direct causal role for the immune response in the development of septic shock. A closer look suggests that septic shock is the result of a generalized build-up of hydrogen peroxide, a toxic cellular by-product generated as a consequence of the hypermetabolic state that accompanies a systemic immune response. This finding points to the systemic accumulation of hydrogen peroxide as a significant risk factor for the development of septic and non-septic shock syndromes.?

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1 year ago

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Karl Brennan

Amazing but simple in design. I imagine if we could prophylacticly treat patients as the present in the ED, I think we could put a real dent in Sepsis related illnesses. If it doesn’t physically effect the patient and are benign medications why hold it back? Simplistic and effective that’s just the Rx

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1 year ago

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Jen H

Fantastic article! Thank you for these pearls…

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1 year ago

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Roger Browning

I hope the more rigorous trials to follow confirm these preliminary findings …… we all do,
However does anyone remember cold fusion? Activated protein c? Decompressive craniectomies?
Some commentators state what harm could it cause ? Anyone heard of the FEAST trial surrly a bolus of fluid wouldn’t cause harm there…
Unblinded studies are so open to confounding and bias we need to be excited by these findings but rigorous in our attempts to confirm them before changing practices.

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1 year ago

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Rohan Bussell

Private GPS, private clinics, vitamin bars, alternative/integrative practices, and probably private individuals, have been using IV Vitamin C in various forms for a long time…im sure if there were significant side effects that would lead to malpractice there wouldve been cases of that on google.
Interesting to note that Marik referred to a couple of hospitals being successfully sued for drowning their patients with the ‘fluid bolus resuscitation’….it says: “This trial found that saline or albumin fluid resuscitation increased mortality by almost 50%. “. Lol…no wonder Marik was disdainful of it.
Its perfectly understandable that experimental treatments are used to try and save people, fortunately in this case Marik had the right idea and experimented with something that has a reported history of working…the phase 2 RCT is already under way for an ascorbic acid based protocol, so that will be very interesting.

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1 year ago

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Rachel Heap

the places that you mention MIGHT have spotted significant adverse events, or worrying trends, IF they had any means to measure, report or analyse them. But alternative practices and practitioners blindly dole out their treatments to desperate punters for cash, and when bad things happen, their unfortunate marks end up in mainstream medical care, and the link between the two is missed. The practitioners don’t hear how their unfortunate patents ended up, there is no tracking of trends or end points, and there certainly isn’t any good quality research or trials into effectiveness OR safety. Just because something is done a lot, and has been done for a while, does not mean it is safe. Absence of evidence is after all, not evidence of absence. And for so many alternative practices there is simply not only little or no evidence of benefit, there is also no evidence of harm (because it isn’t measured).

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1 year ago

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Greg

It seems that both sides are pretty entrenched with their opinions, and as youve mentioned, both are right for now. I’m wondering if we’re all missing the point though. Shouldn’t our jobs Be to sort through all the data, present it to the patient/family with all the benefits, risks, degree of unknown and ultimately let them decide?

Greg
4th year medical student who doesn’t know how the world works yet

Noooooooo!!!!! Good on you for commenting Greg. You have accurately summed up the ongoing argument but I must disagree with your conclusion about how we should present this controversy to patients or their surrogate decision makers (SDMs). Doctors make decisions. Even in the shared-decision-making model of care that we should all be using, doctors make decisions. That is why we’re (usually) paid more than a lot of other people – because we make decisions and take responsibility for those decisions. If there is genuine uncertainty about which of the treatments on offer is the right one for a patient, then all appropriate options should be discussed (note that treatments which are deemed inappropriate need not be discussed) but this presentation of options should ALWAYS be accompanied by a recommendation from the doctor. To simply bombard patients or SDMs with a barrage of options and get them to pick one is simply an easy way out for us. We have been to medical school, they haven’t. For further information on shared decision making see this joint statement from the SCCM and ATS: https://www.ncbi.nlm.nih.gov/pubmed/26509317 And this opinion piece from the NEJM: http://www.nejm.org/doi/full/10.1056/NEJMp1201202#t=article Anyway, great comment. I hope this ongoing discussion inspires you.… Read more »

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1 year ago

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.sigrid nitschmann

Why are still so many people so ignorant about vitamins. Vast amounts of people have suffered and died needlessly for hundreds of years because of vitamin and nutritional deficiencies eg scurvy. Nutrition should become a larger part of the physicians education. It is not just a matter of whether you believe in vitamins or not

The method of action of IV Vitamin C is as a pro-oxative. Levin describes in detail how it functions and why it works. The fact that this is not one of the most frequently used treatments in hospitals for infection and cancer is an indictment of “modern” medicine. Regimes like Dr. Marik’s if rapidly adopted could increase survival at rates not seen since the discovery of penicillin. He should be lauded as a bold pioneer. Good for you Josh to publish these studies and information. Treatments like this will help save health care in the U.S.

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1 year ago

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davea0511

incidentally his infusion rates are too low to exhibit pro-oxidative effect, despite being by IV. There are many mechanisms taking place to exhibit this positive response, and they are well known, dealing with redox of the epithelium and improved messaging, repair, and decreased inflammation.

What's Your Job?

BioMedical Engineer

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1 year ago

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Huib Schut

I am always taken aback by the huge resitance to simple Solutions.
When a large pharmaceutical company would publish these results combined with slik marketing and an absurd pricetag it would be received as a great innovation.
Now , instead, the quest for flaws is launched..
Come you academics , simple solutions can work.
Since no harm is done with vit C it is on the brink of unethical to call for randomized trial.
Let say you wife was diving deep in septic shock in which group in the trial would you like her to be……..
And for evidences based medicin… We do use Davinci robot surgery as a big inivatiion for example. Prices of the device, maintenance and disposables are mind Blowing, marketing is great. Evidence is zero, or rather evidence is that is does not improve patient outcomes and poses larger risks. ( just one of many examples!)
So give your patients Vit C instead of letting them die.

It amazes and worries me that people genuinely think these data mean something and are strong enough to advocate treating patients. First, the argument that it can’t do harm is intellectually destitute. There are loads of things that we don’t think harm patients until we study them properly. There is also the harm that results from getting our nurses to spend their time giving useless treatments. “The results are so dramatic you don’t need a trial”. Randy Chestnut (of traumatic coma database fame) came to our CTG meeting in Noosa when we were planning the DECRA (early decompressive craniectomy) trial. He said we would never do the trial because once people started doing DC the result would be so dramatically good that everyone would just do DC as he did. Well, DECRA was done and guess what, early DC harms patients http://www.nejm.org/doi/full/10.1056/NEJMoa1102077 “Vit C levels are low is sepsis so replace it” Same is true of Protein C but in large RCT Drotrecogin alfa (activated) (Xigris) did not reduce mortality in patients with persistent septic Shock http://www.nejm.org/doi/full/10.1056/NEJMoa1202290 and it was withdrawn from market The other trials referred to are TINY (not small – TINY) and the results unreliable please read… Read more »

Ok… let me trace out this line of logic, step by step: (1) Using Xigris was a big mistake, we should never use a drug supported by such scanty evidence. It made us all look stupid, and we hate looking stupid. (2) Xigris was shown to be effective in the first multicenter RCT, but not the second multicenter RCT (3) Therefore, we should never use a therapy that isn’t supported by two multi-center RCTs (4) Virtually no therapies in critical care medicine are supported by two multi-center RCTs (5) We should sit around twiddling our thumbs while our patients die. Spend a day in the ICU, and for every decision you make consider how many multi-center RCTs support that decision. The vast majority of the time, the answer will be: zero. Demanding proof for everything we do in the ICU is intellectually correct and sounds smart. However, at a pragmatic level, this isn’t very helpful. At some point we are generally forced to make a guess regarding risk vs. benefit. That guess should be based on the best available evidence, but ultimately it ends up being a guess. That’s the nature of the beast. This isn’t preventative cardiology, it’s critical… Read more »

“(4) Virtually no therapies in critical care medicine are supported by two multi-center RCTs
[…]
Spend a day in the ICU, and for every decision you make consider how many multi-center RCTs support that decision. The vast majority of the time, the answer will be: zero.”

Even if the above would be true (it really isn’t), shouldn’t you try to rectify it, instead of expanding it?

Just the thought of more specialties starting to shoot from the hip, the intensivist way (btw, behind the excuse of rapid life-or-death decision making there’s a bit of a God complex imho) is giving me shivers.

Of course knowledge needs to be expanded. I applaud the work of investigators and trialists (including Drs. Finfer, Marik, and Natarajan) who expand our knowledge basis. As a clinician, my job is to use whatever knowledge exists to the best possible advantage to treat patients.

I just admitted that I spend all day making educated guesses – this is not a “god complex.” God doesn’t guess.

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1 year ago

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Michael Jasumback

Josh,

My concern is that we consider this to be “knowledge”, i.e. ascribing to it a degree of validity that is not appropriate. As has been commented ad nauseum, single center, fraught with potential bias etc. What is most concerning is that this is being accepted as either true or false when the data available are not nearly this definite. As you pointed out, it is much more likely that there is an effect, but not as significant as this case series reports.

Thank you!

Mike

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1 year ago

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Fraser Mackay

Glad to see so much curiosity and passion out there. My thoughts are much the same as Chris Nickson and others. Certainly not sold on the results, and definitely a defender of the scientific method, which was not used in this article. Would welcome actual data and rigor before changing my practice (Finishing ICU fellowship in a few months). Also, (Josh) Scurvy WAS put through a multi-center RCT. Multiple naval captains on multiple ships over a series of years tried many remedies prospectively. In fact, if they had listened to physicians at the time, they would have gotten to the solution faster with better experimental designs. Captain Cook was actually convinced it was malt that was curative, only later to be proven wrong (to the detriment of his crew, unfortunately). (http://www.bbc.co.uk/history/british/empire_seapower/captaincook_scurvy_01.shtml) If you think about it, this is one of the best arguments against Merik (and his supporters). Scurvy was rampant with high morbidity and mortality, and the solution was something cheap, easy and efficient. However, people didn’t correctly apply the scientific method and incorrectly assumed they had an answer based on anecdote and cohort based experience. It wasted money, resources, and most importantly time. Many died but probably didn’t… Read more »

I think some folks are really misunderstanding the nature of this debate. We can all agree on the following: (1) It is unproven whether vitamin C works (2) more research is needed (RCTs) (3) it is premature to make this a standard of care (4) the scientific method is good The question is solely what to do in the interim until further studies are released. That is purely a risk/benefit estimation based on available evidence. I disagree with you that the “scientific method was not used” in Marik’s study. There are all sorts of different types of studies with different levels of evidence (ranging from observational to RCT). It is wrong to say that only RCTs are using the “scientific method” Multiple ships performing ad-hoc single-center studies over a period of years doesn’t equal a multi-center study. The concept of a prospective multi-center study didn’t exist during that period of time. The real issue here isn’t pro/con science, but really just early-adopters vs. late-adopters. That issue will never be resolved, which is one reason that there are about 70 comments here and we haven’t made much progress. If you are a late adopter that’s fine, probably most doctors are so… Read more »

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1 year ago

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davea0511

This is why I believe in giving all newly approved treatments a probation period where they are watched very closely and perhaps given only partial insurance coverage (say 80%), and then reviewed quarterly for 2 years. If still looking good at that point it is given the full blessings of the FDA. Should be the case with all newly approved treatments.

Hi. I love this article!
Finally, not another RCT about the perfect fluid or another new scoring system.
We should never forget to be good spectators and curious.

I know this is a very hot topic right now and i enjoy reading all the comments and thoughts.
Are there any ideas about giving the marik cocktail as early as possible?
For e.g. in the ED or even the prehospital phase?

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1 year ago

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John Cronin

Great post as usual Josh. Regardless of whatever we think here, I can only imagine that smart triallists out there are already putting protocols together to do an RCT (multi center or otherwise) on this. That is surely happening. And ethics committees out there will I would imagine have no trouble giving approval given how important this condition is and the fact that there is this study out there that is very interesting and hypothesis-generating. However I think those same committees will agree that there is still clinical equipoise here. Is it the combination that works or is it two of the three? Do the steroids help at all in terms of improving mortality? Furthermore this idea that many people seem to be accepting that this cocktail has almost no adverse effects I don’t buy. As Simon Finfer alluded to we will be using up valuable nurses’ time to get these medications drawn up and given. Also we will be using up what may be potentially precious IV ports. I’m an emergency physician and I will see these patients in Resus – sometimes getting good IV access can be very challenging. If this cocktail does turn out to be the… Read more »

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1 year ago

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Grant Price

Interesting post Josh. So cards on table, I think this sounds too good to be true and want more evidence. Here is my reason why

It is very common practice in my part of the world that many patients are already started on thiamine as alcohol excess is extremely common in the Scottish critical care population (we use a drug combination called pabrinex-which also contains 0.5g of vit C anyway 8h for at least 3 days). In patients with refractory septic shock noradrenaline, vasopressin and steroids are usual care
So they already get hydrocortisone @ 200mg, larger doses of thiamine than Dr Marik (750mg/day) and less Vitamin C (1500mg/day) and yet they still die. This is especially true in our decompensated alcoholic liver disease patients who will ALL get pabrinex as described above and usually have sepsis as the trigger for decompensation. Our outcomes for these patients are no better or worse than other comparable units.

So are my septic shock patients dying due to an inadequate amount of vitamin C? It seems implausible.

Or are we talking about other septic patients with different co morbidity?

I think we all agree that more evidence is needed, and hopefully we will see more coming soon. With regards to your comment, two thoughts.

First, gut absorption of vitamin C is saturable *and* vitamin C consumption is increased in sepsis. 0.5 grams TID of vitamin C is unlikely to achieve adequate vitamin levels here. The pharmacokinetics has been worked out (there are some references to this in Marik’s manuscript). I looked over this literature a few weeks ago, when considering whether it might be possible to modify the cocktail to use oral vitamin C (which is cheaper and easier to do). Unfortunately, this doesn’t seem to achieve adequate blood levels of vitamin C.

Second, many cirrhotic patients die from processes other than sepsis (e.g. decompensated hepatic failure, hepatic encephalopathy, hepatorenal syndrome, alcoholic hepatitis). It’s highly doubtful that vitamin C could stop these processes. Vitamin C might be a treatment for sepsis, but it’s not a panacea that will cure all organ failure.

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1 year ago

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Ramesh Natarajan

You need a minimum IV dose of 3 grams of vitamin C to restore normal circulating levels. In sepsis, it gets consumed very rapidly.. Your dose of 1500mg per day is insufficient. Also thiamine is required for prevention of vitamin C conversion to oxalic acid and subsequent formation of kidney stones. Thiamine ensures conversion of vitamin C to carbon dioxide by being a cofactor for glycine amino transferase.

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1 year ago

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Grant Price

Hi Josh and Rajesh thanks for your responses. The pabrinex is given intravenously so GI absorption not relevant. My ICU residents will place almost anyone on pabrinex iv especially those who have an alcohol history (many of them) and they don’t all have cirrhosis. I used the decompensated alcoholic liver disease example as this group do routinely get iv pabrinex.
Quite rightly you say it’s not a panacea, you describe well the issue of determining whether someone dies of sepsis or perhaps something else. My other patient group who presents similar difficulties are major burns who also ubiquitously will be on pabrinex iv .

Maybe they are being underdosed as per Rajesh, or maybe it’s more complex than that. I hope you are right and it’s a simple fix. Looks like dose, timing, As well as optimal patients likely to respond to this intriguing finding of Paul Marik.

Once again thanks for your blog posts, I really enjoy them.

Grant Price, Edinburgh

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1 year ago

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Grant Price

Sorry sent before edited. Meant to say “….more needs to be elucidated on Paul Mariks intriguing observation. Probably best done in specific groups in a RCT to avoid bias, or do we just exclude the higher risk “septic” patients that I have described.

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1 year ago

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Dave E

Dr. Price, I think your question of are your patients dying due to inadequate Vit C is answered in Marik’s video above – YES it’s too little. His cocktail provides four times the amount you give and his basic science review stresses the importance of high doses. Thus the reason oral routes cannot be effective and even with intravenous routes, higher doses seem to be required. Again, he says the steroids won’t work if the Vit C concentrations aren’t high enough, so the fact that you have equivalent steroid doses is irrelevant per Marik. From my interpretation of his presentation, the thiamine, though important, is a lesser player in all this and has been suggested to be ineffective unless the patient has a demonstrated deficiency. So. Can you use the 10cc ampule of pabrinex q6 hrs on EVERY septic pt for a month or so and report back to us on how it works? 😉 And on a side note, Marik uses fluid restrictive strategy. I applaud his hospital CEO for letting his hospital get dinged by CMS for likely having poor SEP-1 compliance in the name of improved pt outcomes. Between the recent NEJM article from the PRISM authors… Read more »

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1 year ago

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David S. Fedson, MD

The findings of Marik et al are intriguing and need further study. Not mentioned in this discussion is how Vitamin C (with or without thiamine) might actually be working. Most intensivists know that endothelial barrier integrity is lost in most septic patients. This is shown in the higher mortality experienced by septic patients who receive higher volumes of IV fluid replacement. The need to give more IV fluids probably reflects a greater degree of vascular permeability, and this underlying abnormality in endothelial barrier integrity is what needs to be corrected. Interestingly, this can probably be accomplished by treating with other inexpensive generic drugs. In patients with CAP and influenza, inpatient treatment statins and angiotensin receptor blockers (ARBs) is associated with significantly reduced 30-day all-cause mortality, and combination treatment is probably better than single agent treatment. Recently in Sierra Leone, combination treatment of Ebola patients with atorvastatin and irbesartan was reported to be associated with “remarkable improvement” in mortality. Among approximately 100 consecutively treated patients, only three are known to have died. These findings have not been publicly reported by the physicians who administered treatment. Moreover, the suggestion to study this approach to treatment was forcefully rejected by WHO and international… Read more »

[…] level for vitamin C–just to catch us all up to speed while the news / evidence develops. The EMCrit and PulmCrit posts are certainly deeper dives into the purported vitamin C deficiency abnormalities of […]

In the study 47 patients in the treatment group received Solucortef for severe sepsis/septic shock.
Is it standard practice to use steroids for patients with severe sepsis? The dose of Vasopressin .04 units/minute seems to be at odds with the guidelines suggesting .03 units/minute.

Thanks for the excellent review. A few thoughts that came to mind: 1. The “bundle” approach is not necessarily harmful. We have enough negative studies of single agents to justify studying bundles, especially if there is physiological evidence supporting a synergistic mechanism. We should probably be doing more bundle studies, not less. 2. The focus on metabolic resuscitation is justified. We are reaching a point where attempts to improve hemodynamic resuscitation have come to a dead end. Therapies aiming at reversing tissue and cell-level dysfunction are more likely to be fruitful than small incremental changes to existing resuscitation protocols. 3. The enthusiasm borders on proselytism and is slightly disconcerting, especially in the context of an unblinded study. We know that steroids hasten reversal of shock, and we have all seen patients improve 2h after getting a stress dose of hydrocortisone. Are the vitamin C and thiamine really adding anything? 4. We know that there is no mortality benefit to steroids in sepsis all-comers, but many still think that there may be a mortality benefit in an as-of-yet unknown subgroup. If, due to unmeasured variables, patients in the treatment group were more likely to respond to steroids (or inversely, that patients… Read more »

[…] thoughts from the Vitamin SCepTic post and our contribution to the SGEM work on the topic. However, I thought Josh Farkas did a brilliant job with distilling the evidence here, as well as the scientific rationale and plausible mechanism. There was real detail in that post […]

There is currently better quality evidence for the use of “Shenfu Injections” for sepsis ( https://www.ncbi.nlm.nih.gov/pubmed/28029485 ). Perhaps we should all default to IV ginseng/aconite for sepsis until such time better conclusive evidence comes to light.

I hear “healing incantations” might work too… probably would not cause much harm… I better practice my singing voice

There are currently 169 pubmed citations regarding sepsis and vitamin C, with additional article about other aspects of critical care. If you’re suggesting that there is more evidence regarding shenfu then you’re simply not aware of the existing body of evidence about vitamin C.

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1 year ago

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Peter Lipowicz

No, the shenfu injections did not reduce mortality according to the study results.